The activity of cytosolic Phospholipase A2 (cPLA2) may be altered by calcium or by phosphorylation of serines in the cPLA2 molecule. A dual hybridization system in yeast was used to identify protein-protein interactions that might also be involved in the modulation of cPLA2 activity. Using this system, we identified a member of the S-100 family of protein as interacting with cPLA2. In in vitro assays, this protein, p11, was found to inhibit phopholipase A2 activity. Immunoprecipitation of epithelial cell lysates using anti-cPLA2 antibody coprecipitated p11 protein. Antisense inhibition of production of this protein increased arachidonic acid release from airway epithelial cells. Therefore, p11 appears to be capable of modulation of cPLA2 activity. In addition, this protein is inducible with corticosteroid treatment.